Xenotransplants: finding a suitable donor

The pig could be a surrogate organ donor for human transplantation, but what are the complications?
14 February 2022

Interview with 

Megan Sykes, Columbia University

PIG

A pig

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Scientists are trying to develop ways to grow replacement human organs in the laboratory, whilst others are developing ways to increase the numbers of donor organs that are fit to be transplanted. But, in the meantime, researchers are turning to animals, particularly pigs, as one way to address the shortfall. Chris Smith and Adam Murphy find out more... 

Megan (01:05) - We all have antibodies that recognise pig cells, and those are called natural antibodies. That doesn't exist against other human tissues and cells unless we've had some prior exposure. There are also other parts of the immune system, like the T-cell response, that exist for any foreign tissue or organ that is quite strong against xenographs. And finally, there are what we call innate immune responses from cell types that we call natural killer cells and macrophages that are particularly powerful against xenographs.

Chris (01:48) - So what happens, Megan, if we put just a piece of animal tissue, an animal organ, into a human and we just let the immune system do what it does normally without any kind of drug control or anything.

Megan - Well, if there was no drug control, and say it was a pig organ, and no genetic modifications had been performed, then antibodies in our circulation would immediately bind to the cells lining the blood vessels of that pig organ, and that anti antibody binding would initiate a very dramatic process called hyperacute rejection. Within minutes to hours, those blood vessels would be clotted off and the organ would not have any blood flowing to it and it would die. There were some transplant done initially with non-human primates and these same dramatic antibody effects didn't happen in those combinations. But, of course, there are many problems with using non-human primates as an organ source: some of them are endangered species, there are ethical problems with using them, and there are many infectious risks associated with using non-human primates - so that's pretty much been discounted. The pig, on the other hand, is closer to being the right size, especially if you use miniature pigs which we have in our centre, and they have similar physiology to humans and the risks are actually much more manageable.

Chris - How have you therefore sought to overcome what the immune system naturally wants to do to foreign tissue like that from a pig?

Megan - Our approach really began with the development of nuclear transfer techniques with the famous sheep Dolly back around the turn of the century. In the early 2000s, we and another group were able to use that approach to "knock out" of the pig genome the gene that creates a critical enzyme that creates a critical target that is seen by the vast majority of those natural antibodies that bind to the cells lining the blood vessels. By making this early genetic modification to eliminate this enzyme, we eliminated that target on the endothelial cells of the pig - that was a big step. Our group is working on inducing immune tolerance, not only the ones that are targets of antibodies, but also the targets of T-cells and natural killer cells.

Chris - So, in essence, you are both blinding the immune system to the presence of the new tissue because you have removed from it targets that it would normally regard as hostile, and at the same time you then introduce the new material to the immune system saying, "no, this is friend not foe." How do you persuade the immune system that this is friend not foe?

Megan - Well, we have two methods: one involves removing, from the recipient, the organ that produces T lymphocytes - that organ is called the thymus - and putting in the thymus from the pig. So, in that pig thymus, the T lymphocytes learn that the pig, as well as the human recipient, are both self.

Chris - Can I throw a spanner in the works and say, if you're putting pig tissue in, even if it's a thymus, how do you stop the thymus being rejected before it persuades the immune system it's all right,

Megan - Good question. You have to eliminate the T lymphocytes that are already there in the body so that you're starting with a clean slate.

Chris - I'm with you. And what was the second step.

Megan - With the second approach, we can actually educate the B-cells as well as the T-cells to think that anything on that pig is self so that these lesser targets of antibodies are no longer targeted because the B-cells that see those targets get tolerized as well.

Chris - Obviously the long term goal is we grow new organs for people tailor-made to them, or at least compatible with them, and we don't need to dip into animal reservoirs to solve our problem. But, in the near term, do you think that this has legs, this approach? Using very physiologically similar animals like pigs?

Megan - I do - I think it has legs. I think that bioengineering is making great progress and stem cell biology is making great progress, but the complexity of making a functioning organ from scaffold and cells has not yet been surmounted. It's going to work one day, but that day is quite far off. By that time we may have worked out tolerance to pig organs so well that that will be routine and that will solve the problem.

 

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